Frailty and delirium in hospitalized older adults: A systematic review with meta-analysis

Abstract Objective: to estimate the prevalence and synthesize diverse evidence about the relationship between frailty and delirium in hospitalized older adults. Method: a systematic review with meta-analysis in which observational studies conducted with older adults about frailty, delirium and hospitalization, were selected without time of language restrictions. The search was conducted in the MEDLINE, EMBASE, CINAHL, Scopus, Web of Science and CENTRAL databases during August 2021. The precepts set forth by the Joanna Briggs Institute (JBI) - Evidence Synthesis Groups were followed. The meta-analysis model estimated the relative risk corresponding to the prevalence of frailty and delirium. The inverse variance method for proportions was used to estimate the prevalence values and relative risks for binary outcomes. Results: initially, 1,244 articles were identified, of which 26 were included in the meta-analysis (n=13,502 participants), with 34% prevalence of frailty (95% CI:0.26-0.42; I 2=99%; t 2=0.7618, p=0) and 21% for delirium (95% CI:0.17-0,25; I 2=95%; t 2=0.3454, p<0.01). The risk for hospitalized older adults to develop delirium was 66% (RR: 1.66; 95% CI:1.23-2.22; I2=92%; t2=0.4154; p<0.01). Conclusion: 34% prevalence of frailty and 21% of delirium in hospitalized older adults, with frailty being an independent risk factor for developing delirium, with an increased chance of 66% when compared to non-frail individuals.


Introduction
Older adults constitute a unique population segment in hospital care, and the assistance team must be aware of the particularities of this age group, especially the syndromes, in order to detect and treat them early in time (1) . Physical frailty deserves to be highlighted among such conditions due to its multicausal nature, being defined as follows: "a clinical condition characterized by increased vulnerability in the individual when exposed to internal and external stressors, and is a major contributor to functional decline and early mortality in older adults" (2) .
In the scoping review, 204 studies were evaluated on the theme of frail older adults hospitalized with acute diseases, 14% from the geriatrics and emergency areas and 11% from the general practice. Of the 204 studies, 67% identified frail participants using the "Frailty Phenotype", the "Clinical Frailty Scale" (CFS) and the "Frailty Index" (12% each). In this review, 74% of the studies showed a correlation between frailty and the "morality" and "hospitalization time" outcomes (3) .
Delirium is another condition that affects the hospitalized aged population. It is a form of acute brain dysfunction (4)  is "a mental disorder of acute onset and fluctuating course characterized by disturbances of consciousness, orientation, memory, thinking, perception and behavior" (5) .
It is associated with a decrease in functional status, to institutionalization, to premature mortality, and to an increase in health-related costs.
One-third of the clinical inpatients aged at least 70 years old have delirium; the condition is present in half of these patients on admission and develops during hospitalization in the other half (6) . Its etiology is multifactorial, with an incidence rate of 83% in hospitalized older adults (5) .
Frailty and delírium share responsibility for the increase in morbidity and mortality (7) , in addition to prolonged hospitalization times and long-term functional and cognitive impairment (8) . In an emergency service, it was verified that delirium had 3 time more chances to occur in frail than in non-frail older adults after adjustments for age and gender (9) .
A prospective cohort study conducted in Italy with 89 hospitalized older adults evaluated delirium, attention performance and frailty status in a geriatric emergency department. To evaluate the patients' attention, they were asked to list the months of the year backwards (MOTYB test), then list the days of the week backwards (DOWB) and count from 20 to 1 (BC). The mean age was 83.1 ± 6 years old and prevalence values of 47.19% (n=42) and 41.70% (n=37) were observed for frailty and delirium, respectively. There was an association between frailty and delirium (RR: 4.90; 95% CI:2.01-11.94) (10) . The association of the frailty level on admission to the emergency service with hospital complications, including delirium, was evaluated in the emergency room of two public general hospitals in Mexico City -Mexico. This secondary analysis of the cohort study conducted with 548 individuals presented a mean age of 76 ± 7.2 years old. The presence of delirium according to frailty stratification was 0% (frailty index <0.2), 3.4% (frailty index from 0.20 to 0.39), 6.2% (frailty index from 0.40 to 0.59) and 23.2% (frailty index >0.60); thus, frailty was positively associated with delirium (β = 3.68; 95% CI: 1.53-5.83, p<0.01) (11) .
The literature regarding delirium and frailty in hospitalized older adults is scarce, being mainly limited to the mortality outcome or to specific subgroups such as hospital sectors or related to surgical procedures.
Relevance of the topic is noted due to the fact that physical frailty and delirium proved to be two of the most complex management problems among hospitalized older adults. In the clinical practice, occurrence of these conditions is constantly observed among hospitalized older adults, and they are related to negative outcomes such as delayed functional recovery, disability (12) and death (13) .
Given the above, the objective of the current study was to estimate the prevalence and synthesize diverse evidence about the relationship between frailty and delirium in hospitalized older adults.

Method
This is a systematic review with meta-analysis, based on the precepts set forth by the Joanna Briggs Institute (JBI) -Evidence Synthesis Groups (14) . The

Research strategy
In order to formulate the guiding question and design the search for studies, the PEO (P -Population or Patients; E -Exposure; O -Outcomes) (15) was used, where P (Frail older adults), E (Hospitalization) and O (Delirium).
After applying the PEO strategy, and to guide the search strategy terms, the following question was formulated: Which is the relationship between frailty and delirium in hospitalized older adults? www.eerp.usp.br/rlae 3 Cechinel C, Lenardt MH, Rodrigues JAM, Binotto MA, Aristides MM, Kraus R.
The inclusion criteria to select the study were as follows: observational studies, including prospective and retrospective cohort, case-control and cross-sectional studies; presence of the variables of interest: "frailty" and "delirium"; developed in a hospital setting; involving older adults aged ≥ 60 years old; and published in any language with no limitation regarding publication date.
The exclusion criteria for the studies were as follows: not categorizing patients as frail and non-frail, case reports, letters to the editor, abstracts in conference proceedings, dissertations, theses and monographs.

Data extraction and synthesis
The total number of articles found in each database and the sum of all databases were recorded in the PRISMA flowchart (16) , as well as the entire selection process and reasons for exclusion. The results of the searches were imported into the Mendeley ® software to store, organize and classify the references. In addition to that, it was possible to remove the duplicates in the reference manager.
The database search was performed by the main researcher, who then divided the titles of the articles between two reviewers who performed the evaluation independently.
The titles of the articles were analyzed and the ineligible studies were excluded. In the subsequent stage, the abstracts were read and the ineligible articles were removed after applying the eligibility criteria.
The abstracts evaluated were returned to the main researcher, who made all articles available in full-text format to the reviewers for evaluation of the eligibility criteria. To minimize a possible bias in selection of the studies, a refinement procedure was performed by two independent reviewers seeking 100% agreement, and a third reviewer evaluated the possible divergences that occurred in the selection of abstracts to make a final decision on their inclusion or exclusion.
Data extraction was performed in a Microsoft Excel ® table to compile the data from the studies included. It was constructed to cover the previously defined eligibility criteria using the Joanna Briggs Institute (14) instruments, which included the following: author's name, year, country, patient's profile, purpose of the paper, sample size, study design, frailty evaluation instrument, delirium evaluation instrument and outcomes. The final references of the primary studies included were also evaluated manually, in an attempt to find relevant articles that might be added to the review.
To describe the intensity of agreement between the reviewers, the Kappa measure was used, which is based on the number of concordant answers, i.e., the frequency at which the result is the same between the reviewers (17) .
For this study, the Kappa agreement index was 0.892, which shows strong/almost perfect agreement between the reviewers.
The data analyzed for the meta-analysis were the following: total number of patients, number of frail and non-frail patients, number of patients with delirium and their combined effects. The meta-analysis model estimated the relative risk corresponding to the prevalence of frailty and delirium. The "pooled effects" were estimated using the inverse variance method of proportions to estimate prevalence values and relative risk for the binary outcomes, with 95% confidence interval, and represented in Forest plots.
Heterogeneity across the studies was tested by means of the I 2 test, considering it significant when p<0.05. The alternative hypothesis of the heterogeneity test is that variability/heterogeneity is significant; therefore, fixed or random effects models were chosen based on acceptance or rejection of the null hypothesis. All the analyses were performed in the R 4.1.1 environment (18) .

Evaluation of the methodological quality
The eligible studies were critically evaluated by two independent reviewers regarding their methodological quality by resorting to the Joanna Briggs Institute (JBI) scale. Any and all disagreements were solved by means of a discussion with a third reviewer. On a scale consisting of nine criteria, studies that met from zero to three criteria were considered to be of low quality, those that met from four to six criteria were considered to be of medium quality, and from seven or more were considered to be of high methodological quality. The evaluation scores in relation to the methodological quality showed that most www.eerp.usp.br/rlae

Ethical aspects
As this study resorted to articles from databases and did not involve human beings, it waived approval by the Research Ethics Committee, according to National Health Council Resolution No. 510/2016 and the ethical regulations in force (42) .

Results
The database search resulted in 1,244 studies in all eight databases; 748 were excluded for being duplicates and 496 were selected for reading their titles and abstracts. Of these, 398 articles were excluded after reading their titles and 21 after reading the abstracts, resulting in the selection of 77 for full-reading. A total of 51 were excluded after this stage, resulting in the inclusion of 26 articles. No new eligible studies for the review were found after consulting the references of the primary studies. Figure 2 shows the flowchart of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method used to illustrate selection of the articles for this systematic review (16) . www     In Figure 4, it can be seen that the prevalence of   In Figure 5, the relative risk of frailty and delirium was 1.66 (from 1.18 to 2.22; I 2 =92%; t 2 =0.4154, p<0.01). Each line represents a study, and the last one represents the combination of the results (meta-analysis), which is symbolized by a "diamond".
Note: Heterogeneity was tested by means of the I 2 test, considering it significant when p<0.05. *CI = Confidence Interval

Discussion
In this systematic review with meta-analysis, it was identified that frailty was independently associated with an increased risk of delirium in hospitalized older adults: 1.66 (95% CI: 1.23-2.22 I 2 =95%; t 2 =0.4154, p<0.01).
The prevalence of frailty in hospitalized older adults was 34% (from 26% to 42%) and that of delirium across the studies was 21% (from 17% to 25%).
The scarcity of studies evaluating frailty as a predisposing factor to delirium (10,21,(37)(38)41) was an unexpected finding of this paper, as the association between these conditions is accepted in the clinical  (24) .
The instruments used to evaluate frailty showed great heterogeneity, with preference given to the use of multidimensional instruments. Evaluation by Fried's frailty phenotype (32) was used in only one study; however, its markers were used in other studies, which worked with Fried's modified phenotype (19) , or some of its components (gait speed and handgrip strength) (28) . Only one of the studies used a frailty index associated with clinical judgment (26) .
Delirium was evaluated using validated diagnostic instruments and screening tools, with significant heterogeneity across the studies. The screening instrument most frequently used was the Confusion Assessment Method (CAM) (9,13,19,(21)(22)(23)35,38) . Other studies have used the association of CAM with other instruments, such as CAM-ICU (32) and/or DSM diagnostic criteria (38) . Used in critically-ill patients, CAM-ICU was also used separately (39) .
The prevalence of frailty in hospitalized older adults was 34% (from 23% to 46%). The highest prevalence values of frailty were observed in a study conducted in Singapore with 234 older adults with surgical indication in which the association between frailty and residual subsyndromic delirium was investigated: 68% (from 62% to 74%) (27) .  Rev. Latino-Am. Enfermagem 2022;30:e3687.
at examining the MFI discriminatory value to predict delirium and cognitive dysfunction after hip arthroplasty, and 54% (from 62% to 74%) prevalence was observed (40) .
The prevalence of delirium among the studies was 21% (from 17% to 24%). The highest prevalence observed was found in the study conducted in Japan, 48% (95% CI: 40%-56%), with 133 patients that evaluated the association of baseline frailty with postoperative delirium and cognitive change 1 and 12 months after cardiac surgeries (32) . In the prospective cohort study conducted in Italy with 89 older adults, evaluating frailty and delirium in patients admitted to a geriatric emergency service, the prevalence of delirium was 42% (from 32% to 52%) (10) .
The mechanisms surrounding development of delirium in frail patients are complex: these patients experience decreased functional capacity and increased vulnerability when subjected to a stressor, such as major surgery or an acute critical medical situation, making it more likely that they will experience delirium. Frail older adults also have cognitive impairment, which intensifies the risk of delirium (12) .
From a clinical point of view, frailty can be considered a risk factor for development of delirium, although there is still not sufficient evidence that delirium can be a trigger for frailty. When persistent, delirium can be a precipitating factor for deterioration in terms of frailty.
In the evaluation of the hospitalized older adults, frailty should be screened for, as it allows anticipating occurrence of delirium. Likewise, systematic screening for delirium should be performed to identify individuals at risk for subsequent deterioration in terms of frailty (43) .
Active search for the frailty condition in the acute care setting (hospitalized patients) is mandatory, and an individualized approach is required in the management of frail older adults (44) , due to the higher association with hospital complications (45) . as a serious condition that interferes with prognosis (13) .
Frailty is a dynamic entity, and older adults can transition from being robust to being frail (46) . Little is said about the specific approach to physical frailty in the hospitalized patient, with its relationship to morbidities, mortality, and/ or delirium being more evaluated. A comprehensive care plan for frailty should systematically address the following: polypharmacy, management of sarcopenia, treatable causes of weight loss and causes of exhaustion (depression, anemia, hypotension, hypothyroidism, and vitamin B12 deficiency), with strong recommendation, although with too low certainty of evidence (47) .
Although more studies are needed to better clarify the cause/effect relationship between these two conditions, this association has important clinical implications. The presence of frailty should be investigated in hospitalized aged patients, as this condition predicts negative adverse outcomes and requires individualized care. When present, frailty should lead to a search for the presence of concomitant delirium, given the high probability of its simultaneous incidence. In the absence of delirium, evidence-based non-pharmacological measures should be intensively implemented to prevent it (48) , given the high risk for its development.
Programs involving multiple components conducted by different professionals in the prevention of delirium have the potential to reduce complications in high-risk aged patients, thereby improving treatment and long-term quality of life.
The implementation of additional interprofessional teams acting to prevent delirium and providing regular training on the optimal management of delirium is an intervention option. Demonstrating the effectiveness of these programs requires large multicenter studies (49) .
The methodological quality of the studies was evaluated as reasonable to good (not excellent) and they were heterogeneous with regard to study populations and definitions of the variables of interest (frailty and delirium).
The quality levels of the studies evaluated did not influence the association between frailty and subsequent delirium, throughout the day; therefore, it is possible that delirium was undersampled in some studies.
Identification of baseline frailty raises the possibility that it may be a potential therapeutic target in the prevention of delirium in the clinical practice. The results of this review may assist in encouraging early diagnosis of the frailty syndrome and delirium in the hospital setting, guiding prognosis, individualized care plans, and prevention of adverse outcomes.
Efforts should be directed towards mitigation and treatment strategies of delirium with early identification of risk factors (50) , in different clinical and surgical contexts.
Studies of the association between frailty and delirium in hospitalized older adults are still incipient, which highlights the need to investigate interventions for hospitalized older adults with frailty and delirium.

Conclusion
This study showed 34% prevalence of frailty and 21% of delirium in hospitalized older adults, with frailty being an independent risk factor for developing delirium, with an increased chance of 66% when compared to nonfrail individuals.